ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors.
Maria SkamagkiCristina CorreiaPercy YeungTimour BaslanSamuel BeckCheng ZhangChristian A RossLam DangZhong LiuSimona GiuntaTzu-Pei ChangJoye WangAparna AnanthanarayananMartina BohndorfBenedikt BosbachJames AdjayeHironori FunabikiJonghwan KimScott LoweJames J CollinsChi-Wei LuHu LiRui ZhaoKitai KimPublished in: Nature cell biology (2017)
Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSCs and addition of ZSCAN10 to the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) during A-iPSC reprogramming normalizes ROS-glutathione homeostasis and the DNA damage response, and recovers genomic stability. Correcting the genomic instability of A-iPSCs will ultimately enhance our ability to produce histocompatible functional tissues from older patients' own cells that are safe for transplantation.
Keyphrases
- induced pluripotent stem cells
- dna damage response
- cell cycle arrest
- reactive oxygen species
- cell death
- induced apoptosis
- dna repair
- copy number
- endoplasmic reticulum stress
- oxidative stress
- gene expression
- dna damage
- transcription factor
- stem cells
- optical coherence tomography
- kidney transplantation
- pi k akt
- cell proliferation
- signaling pathway
- diabetic retinopathy
- dna methylation
- genome wide
- weight loss
- bone marrow